This study identifies ZFHX3 as a novel causative gene for childhood partial epilepsy and developmental epileptic encephalopathy (DEE). Whole-exome sequencing of 378 patients with partial epilepsy revealed compound heterozygous ZFHX3 variants in eight unrelated cases, including two who evolved from early spasms. These variants were associated with partial seizures, neurodevelopmental abnormalities, and DEE. However, all patients achieved seizure-free status after antiepileptic drug treatment without the use of adrenocorticotropic-hormone/steroids. A Drosophila model with Zfh2 knockdown confirmed the association between ZFHX3 and epilepsy, showing increased seizure-like behavior and neuronal firing. The study also found that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth, which may explain the favorable outcomes in patients. The findings suggest that ZFHX3 is a novel pathogenic gene for childhood partial epilepsy and DEE, and that genetic diagnosis is crucial for precise treatment. The study highlights the importance of understanding the genetic-dependent stages in the evolutionary course of the illness.This study identifies ZFHX3 as a novel causative gene for childhood partial epilepsy and developmental epileptic encephalopathy (DEE). Whole-exome sequencing of 378 patients with partial epilepsy revealed compound heterozygous ZFHX3 variants in eight unrelated cases, including two who evolved from early spasms. These variants were associated with partial seizures, neurodevelopmental abnormalities, and DEE. However, all patients achieved seizure-free status after antiepileptic drug treatment without the use of adrenocorticotropic-hormone/steroids. A Drosophila model with Zfh2 knockdown confirmed the association between ZFHX3 and epilepsy, showing increased seizure-like behavior and neuronal firing. The study also found that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth, which may explain the favorable outcomes in patients. The findings suggest that ZFHX3 is a novel pathogenic gene for childhood partial epilepsy and DEE, and that genetic diagnosis is crucial for precise treatment. The study highlights the importance of understanding the genetic-dependent stages in the evolutionary course of the illness.